Summary of work: The aim of this project is to assess the effects of aging at a behavioral level of analysis, to identify neurobiological mechanisms associated with these effects, and to evaluate interventions that might alter age-related performance decrements. Rodent and nonhuman primate models are tested in a battery of sensorimotor and learning/memory tasks. Neurochemical and neurohistological assays are conducted to determine neurobiological correlates of functional losses. Interventions include various nutritional, hormonal and pharmacological treatments. Multiple genotypes and genetically modified mice are examined to determine possible genetic involvement in age-related behavioral impairment. We have identified various effective pharmacologic strategies for improving learning performance of aged rodents using manipulations of the cholinergic and glutamatergic neurotransmitter systems. The lead cholinergic compound in this effort is the cholinesterase inhibitor, phenserine, which is currently in Phase III clinical trials using oral dosing in patients with Alzheimer?s disease (AD). Given the success of that effort, we have been evaluating a series of novel inhibitors of glycine uptake to overcome a maze learning impairment in rats induced by a pharmacological block of N-methyl-D-aspartate (NMDA) glutamate receptors. Inhibition of glycine uptake should enhance signaling through the NMDA receptor. Thusfar, we have not found an effective compound. The objective of these studies is to design a single compound that delivers inhibition of both glycine uptake and cholinesterase. We believe that this strategy offers greater potential for cognitive enhancement than inhibition of either target alone. We have continued work examining the role of nitric oxide in memory dysfunction. Nitric oxide enhances guanylate cyclase and production of the second messenger, cyclic guanosine monophosphate (cGMP), which in turn stimulates glutamate release. Inhibitors of cGMP-specific phosphodiesterase enzyme type 5 (PDE-5) can enhance cGMP activity. Sildenafil citrate, or Viagra, is one such PDE-5 inhibitor in clinical use for erectile dysfunction. In addition, clinical reports of persons using this compound have indicated cognitive effects which have been demonstrated in animal learning experiments. We have begun to evaluate this compound on maze performance in rats. Although the dose response was complex, we did observe that sildenafil could attenuate a learning impairment induced by a pharmacological block of cholinergic receptors. As a nutritional intervention, we have continued our investigations of the neuroprotective effects of a diet enriched with blueberries, which are high in polyphenolic compounds that can act as potent antioxidants. We found that rats maintained for 3 months on the blueberry enriched diet showed marked attenuation of the maze learning impairment induced by hippocampal injection of the neurotoxin, kainic acid (KA, which acts through glutamate receptors) compared to rats on a control diet, and that their improved performance was associated with less damage to their hippocampus. As another project, we have investigated the long-term effects of learning associated with chronic chemotherapy. Studies of women undergoing such treatments have reported increased cognitive problems. In our studies, female rats receiving monthly injections of cyclophosphamide (cytox) or 5-fluorouracil exhibited marked signs of toxicity; however, instead of impaired learning in two maze tasks, we observed that the rats undergoing chemotherapy showed superior performance compared to controls. Follow-up studies indicate that long-term potentiation (LTP), an electrophysiological index of enhanced synaptic strength, was impaired in rats while they were undergoing cytox treatment, but was actually improved when the rats were allowed to recover for a few weeks consistent with their enhanced maze learning performance. In addition, we found that calcium entry into the neurons treated with cytox are enhanced, but the cells were more vulnerable to glutamate toxicity. Preliminary studies did not find an increased production of erythropoietin in brain, which can be produced in neuroglia, and act as a neuroprotectant. We are now evaluating whether the chemotherapy increased levels of brain-derived neurotrophic factor (BDNF).